Background/Purpose: Calcium pyrophosphate deposition (CPPD) disease results from precipitation of calcium pyrophosphate (CPP) crystals in joints. Prior studies demonstrated that vascular calcification is more common in patients with CPPD compared to those without CPPD. Vascular calcification is implicated in the development of cardiovascular disease, yet studies of cardiovascular risks in CPPD are lacking. We aimed to assess the risk of cardiovascular events and all-cause mortality in patients with CPPD vs. those without CPPD.

Methods: Using a retrospective cohort study design within the national Veterans Affairs (VA) database (2010-2014), we compared the risk of major adverse cardiovascular events (MACE) in US veterans with CPPD vs. veterans without CPPD. CPPD was defined by ≥1 ICD-9 code for chondrocalcinosis or calcium metabolism disorder (712.1-712.39 or 275.49; positive predictive value 91%).¹ CPPD patients were age and sex-matched 1:4 to patients without those ICD-9 codes (controls). Only males were included in the analysis, as MACE was extremely uncommon in females. All subjects had at least 1 healthcare encounter in the 365 days before index date, defined as the first ICD-9 code for CPPD or a matched date for controls, to allow for covariate assessment. Covariates were included if present during the study period prior to MACE.
The primary outcome was any MACE, defined by ICD-9 and/or procedure codes for myocardial infarction (MI), acute coronary syndrome (ACS), re-vascularization, or ischemic stroke. Secondary outcomes included individual types of MACE and all-cause mortality.  We estimated incidence rates (IR) per 1,000 person-years and incidence rate ratios (IRR) for MACE and all-cause mortality. Stepwise Cox proportional hazards regression models were adjusted for traditional cardiovascular (CV) risk factors (hypertension, hyperlipidemia, diabetes, chronic kidney disease, peripheral vascular disease, smoking, obesity, gout, osteoarthritis, rheumatoid arthritis and prior history of MACE).  Kaplan Meier curves and log-rank tests estimated the difference in MACE and mortality rates between groups.

Results: We identified 24,413 CPPD patients matched to 97,591 controls.
MACE occurred in 702 (2.88%) patients with CPPD and 1069 (1.10%) controls (Figure 1). The IR of any MACE was nearly three times higher in patients with CPPD (IR 11.5 [95% CI 10.7-12.4]) compared to controls (4.3 [4.1-4.6]), with IRR 2.66 (2.42-2.93). The IRR for each individual type of MACE was also higher in CPPD vs. controls (Table 1). Findings were similar in adjusted Cox models.
The all-cause mortality rate was higher in patients with CPPD (IR 57.7 [55.7-59.7]) than controls (42.9 [42.0-43.7]) with IRR 1.35 (1.29-1.40). Cox analysis could not be performed because CPPD violated the proportional hazards assumption for mortality. In unadjusted survival analysis, time to death was shorter among CPPD patients than controls (log rank p< 0.0001) (Figure 2).

Conclusion: CPPD was associated with an increased risk of MACE after adjusting for known cardiovascular disease risk factors. Patients with CPPD also had a higher mortality rate compared to patients without CPPD.

1. Bartels CM, et al. J Clin Rheumatol 2015;21:189-92.

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